Biology subjects

Coudray, A.

Publications and source records attributed to Coudray, A..

7 recordsLinked to original sources

bioRxiv2024

Evolutionarily recent transcription factors partake in human cell cycle regulation

The cell cycle is a fundamental process in eukaryotic biology and is accordingly controlled by a highly conserved core signaling cascade. However, whether recently evolved proteins also influence this process is unclear. Here, we systematically map the influence of evolutionarily recent transcription factors (TFs) on human cell cycle progression. We find that the genomic targets of select young TFs, many of which belong to the rapidly evolving Kruppel-associated box (KRAB) zinc-finger proteins (KZFP) family, exhibit synchronized cell cycle expression. Systematic perturbation studies reveal that silencing recent TFs disrupts normal cell cycle progression, which we experimentally confirm for ZNF519, a simian-restricted KZFP. Further, we show that the therian-specific KZFP ZNF274 sets the cell cycle expression and replication timing of hundreds of clustered genes. These findings highlight an underappreciated level of lineage specificity in cell cycle regulation.

cell biology↗

bioRxiv2020

Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

Transposable elements (TEs) constitute 50% of the human genome and many have been co-opted throughout human evolution due to gain of advantageous regulatory functions controlling gene expression networks. Several lines of evidence suggest these networks can be fine-tuned by the largest family of TE controllers, the KRAB-containing zinc finger proteins (KZFPs). One tissue permissive for TE transcriptional activation (termed transposcription) is the adult human brain, however comprehensive studies on the extent of this process and its potential contribution to human brain development are lacking. In order to elucidate the spatiotemporal transposcriptome of the developing human brain, we have analysed two independent RNA-seq datasets encompassing 16 distinct brain regions from eight weeks post-conception into adulthood. We reveal an anti-correlated, KZFP:TE transcriptional profile defining the late prenatal to early postnatal transition, and the spatiotemporal and cell type specific activation of TE-derived alternative promoters driving the expression of neurogenesis-associated genes. We also demonstrate experimentally that a co-opted antisense L2 element drives temporal protein re-localisation away from the endoplasmic reticulum, suggestive of novel TE dependent protein function in primate evolution. This work highlights the widespread dynamic nature of the spatiotemporal KZFP:TE transcriptome and its potential importance throughout neurotypical human brain development.

genomics↗

bioRxiv2020

Ongoing evolution of KRAB zinc finger protein-coding genes in modern humans

BackgroundKruppel-associated box (KRAB) zinc finger proteins (KZFPs) constitute the largest and fastest evolving family of gene regulators encoded by the human genome. Recent data indicate that many KZFPs serve as repressors of transposable element-embedded regulatory sequences (TEeRS) and that the evolutionary turnover of KZFP genes is mainly attributable to the changing transposable element (TE) load of their hosts. However, how natural selection and genetic variation are shaping this process is still poorly defined. MethodsGenetic information was collected from nine primate species and 138,500 human genomes. Gene-wide as well as functional amino acid position specific constraint was calculated across all human KZFPs. ResultsWe found that the most conserved KZFPs, some of which go back close to 400 million years, have been subjected to marked negative selection in the evolutionarily recent past and are very homogeneous within the human population. In contrast, younger, largely primate-restricted family members present evidence of less negative selection than the rest of genome and lower levels of coding constraint, particularly within the sequences encoding the functional sites of their zinc finger (ZF) arrays. We defined 33 sets of KZFP paralogs, which pairwise displayed a broad range of coding constraints differentials, with more recently emerged paralogs usually displaying a higher frequency of putatively deleterious mutations and missense variants within the functional sites of their ZF arrays than their source gene. Finally, we identified three KZFP genes more constrained in the genomes of individuals of African ancestry than in Europeans, with their modes of expression or DNA targets pointing to possible links between these inter-populational genetic differences and regional differences in the prevalence of some diseases. ConclusionsThis work shows how the ongoing selection of KZFPs contributes to modern human genetic variation, in particular through the constraint of putatively deleterious- and missense variants in functional protein sites, and how ongoing interplays between environment and KZFP genes might be impacting the biology of modern humans.

genomics↗

bioRxiv2020

Endogenous retroviruses drive KRAB zinc-finger family protein expression for tumor suppression

Numerous genes are aberrantly expressed in tumors, but its cause remains unclear. Human endogenous retroviruses (HERVs) are repetitive elements in the genome and have a potential to work as enhancers modulating adjacent genes. Since numerous HERVs are activated epigenetically in tumors, their activation could alter gene expression globally in tumors and change the tumor characteristics. Here, we show the HERV activation in tumors is associated with the upregulation of hundreds of transcriptional suppressors, Kruppel-associated box domain-containing zinc-finger family proteins (KZFPs). KZFP genes are preferentially encoded nearby the activated HERVs in tumors and transcriptionally regulated by the adjacent HERVs. Increased HERV and KZFP expression in tumors was associated with better disease conditions. Many KZFPs could suppress the progressive characteristics of cancer cells by downregulating genes related to the cell cycle and cell-matrix adhesion. Our data suggest that HERV activation in tumors drives the concerted expression of KZFP genes for tumor suppression.

cancer biology↗

bioRxiv2019

Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons

In the first days of embryogenesis, transposable element-embedded regulatory sequences (TEeRS) are silenced by Kruppel-associated box (KRAB)-zinc finger proteins (KZFPs). Many TEeRS are subsequently coopted in transcription networks, but how KZFPs influence this process is largely unknown. We identify ZNF417 and ZNF587 as primate-specific KZFPs repressing HERVK (human endogenous retrovirus K) and SVA (SINE-VNTR-Alu) integrants in human embryonic stem cells (ESC). Expressed in specific regions of the human developing and adult brain, ZNF417/587 keep controlling TEeRS in ESC-derived neurons and brain organoids, secondarily influencing the differentiation and neurotransmission profile of neurons and preventing the induction of neurotoxic retroviral proteins and an interferon-like response. Thus, evolutionarily recent KZFPs and their TE targets partner up to influence human neuronal differentiation and physiology. One Sentence SummaryYoung transposable elements and their protein controllers team up to regulate the differentiation and function of human neurons.

evolutionary biology↗

bioRxiv2018

DPPA2 and DPPA4 are necessary to establish a totipotent state in mouse embryonic stem cells

After fertilization of the transcriptionally silent oocyte, expression from both parental chromosomes is launched through so-called zygotic genome activation (ZGA), occurring in the mouse at the 2-cell stage. Amongst the first elements to be transcribed are the Dux gene, the product of which secondarily induces a wide array of ZGA genes, and a subset of evolutionary recent LINE-1 retrotransposons, which regulate chromatin accessibility in the early embryo. The maternally-inherited factors that activate Dux and LINE-1 transcription have so far remained unknown. Here we identify the paralog proteins DPPA2 and DPPA4 as responsible for this process.

developmental biology↗

bioRxiv2018

Detection and benchmarking of somatic mutations in cancer genomes using RNA-seq data

To detect functional somatic mutations in tumor samples, whole-exome sequencing (WES) is often used for its reliability and relative low cost. RNA-seq, while generally used to measure gene expression, can potentially also be used for identification of somatic mutations. However there has been little systematic evaluation of the utility of RNA-seq for identifying somatic mutations. Here, we develop and evaluate a pipeline for processing RNA-seq data from glioblastoma multiforme (GBM) tumors in order to identify somatic mutations. The pipeline entails the use of the STAR aligner 2-pass procedure jointly with MuTect2 from GATK to detect somatic variants. Variants identified from RNA-seq data were evaluated by comparison against the COSMIC and dbSNP databases, and also compared to somatic variants identified by exome sequencing. We also estimated the putative functional impact of coding variants in the most frequently mutated genes in GBM. Interestingly, variants identified by RNA-seq alone showed better representation of GBM-related mutations cataloged by COSMIC. RNA-seq-only data substantially outperformed the ability of WES to reveal potentially new somatic mutations in known GBM-related pathways, and allowed us to build a high-quality set of somatic mutations common to exome and RNA-seq calls. Using RNA-seq data in parallel with WES data to detect somatic mutations in cancer genomes can thus broaden the scope of discoveries and lend additional support to somatic variants identified by exome sequencing alone.

cancer biology↗